Process for the preparation of a furan derivative

Description

[0001] This invention relates to a process for the preparation of a furan derivative.

[0002] The furan derivative of formula (I)

which is known as ranitidine is disclosed in British Patent Specification No. 1565966 as a potent and selective H₂-antagonist.

[0003] The present invention provides a process for the preparation of ranitidine of formula (I) which comprises reacting cystamine of formula (II)

either with a nitroethenamine of formula (III)

where L is alkylthio, e.g. methylthio, or with a compound of formula (IV)

where L is as defined above, followed by reaction with methylamine, to give a disulphide of formula (V)

which is then reacted with 5-[(dimethylamino)methyl]-2-furanmethanol.

[0004] The reaction of the disulphide (V) with 5-[(dimethylamino)methyl]-2-furanmethanol is carried out under acid conditions and conveniently at a temperature within the range 0-100°C. Suitable acids include mineral acids such as hydrochloric or sulphuric acid, hydrochloric acid being preferred. More preferably the reaction is carried out in the presence of concentrated hydrochloric acid, conveniently at an initial temperature of 0­4°C with subsequent heating for a short period at for example 90―100°C. Alternatively the reaction may be carried out in the presence of aqueous acid e.g. 5M hydrochloric acid or 5N sulphuric acid, preferably with heating e.g. at a temperature in the range of 35-50°C.

[0005] In the preparation of the intermediate disulphide (V) cystamine is preferably reacted with the nitroethenamine of formula (III). This reaction may be carried out in the presence of a solvent such as acetonitrile or more preferably water, and conveniently at a temperature within the range of 0° to room temperature. Alternatively cystamine may be reacted with a compound of formula (IV) under the conditions described above, followed by reaction with methylamine at a temperature from ambient to reflux, preferably at room temperature.

[0006] Cystamine may conveniently be generated in situ from a salt such as the dihydrochloride for example by reaction with a base such as potassium hydroxide.

[0007] It is desirable to pass a steady stream of a gas, such as nitrogen or air, through the reaction vessel during preparation of the disulphide.

[0008] If desired the furan derivative of formula (I) once obtained may be converted into an acid addition salt, e.g. a hydrochloride, using conventional methods. Thus for example appropriate quantities of the free base of formula (I) and an acid, e.g. hydrochloric acid, may be mixed in a suitable solvent(s), e.g. an alcohol such as ethanol, or an ester such as ethyl acetate.

[0009] The process of the present invention is advantageous in that it uses cheap and readily available starting materials, and the intermediate disulphide may be readily isolated in pure crystalline form.

[0010] The invention is illustrated by the following Examples.

Example 1

N-[2-[[5-[(Dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine (a) N,N'-bis-[Thio(2,1-ethanediyl)]bis(N'-methyl-2-nitro-1,1-ethenediamine)

[0011] To a stirred solution of 2,2'-dithiobisethanamine dihydrochloride (6.75 g) and potassium hydroxide (3.37 g) in water (150 ml) at 0-4° was added finely powdered N-methyl-(1-methylthio)-2-nitroethenamine (8.98 g). A rapid stream of air was passed through the ice cold mixture for 2h and for a further 2h after the mixture had reached room temperature. The white precipitate which separated was filtered, washed with water than ethanol and ether and dried to give the title compound (8.53 g), m.p. 205-207° decomp.

(b) N-[2-[[5-[(Dimethylamino)methyl]-2-furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine

[0012] To a solution of 5-[(dimethylamino)methyl]-2-furanmethanol (1.72 g) in 5M hydrochloric acid (2.2 ml) at room temperature was added N,N'-bis[thio(2,1-ethanediyl)]bis(N'-methyl-2-nitro-1,1-ethenediamine) (1.76 g) and 5M hydrochloric acid (10 ml). After heating at 40-45°C for 23.5h, tetrahydrofuran (120 ml) and excess anhydrous sodium carbonate was added. The mixture was stood at room temperature for 25.5h then filtered and the filtrate evaporated in vacuo to give an oil (2.8 g). This was chromatographed on silica using methanol- 0.88 ammonia, 200:1 and the appropriate eluate evaporated in vacuo to give an oil (0.37 g). The solid which separated on crystallisation from 4-methyl-pentan-2-one was filtered, washed with 4-methylpentan-2-one, isopropyl acetate and ether to give the title compound (0.09 g), m.p. 67.5-69° which was not depressed on admixture with a sample prepared according to the method of Example 15 in British Patent Specification No: 1565966.

Example 2

N-[2-[[5-[(Dimethylaminolmethyl]-2-furanylmethyl]thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine

[0013] To a stirred solution of N,N'-bis[thio(2,1-ethanediyl)]bis(N'-methyl-2-nitro-1,1-ethenediamine) (1.76 g) in concentrated hydrochloric acid (12 ml) cooled in ice was added 5-[(dimethylamino)methyl]-2-furanmethanol (1.72 g). The mixture was kept at 0―4° for 64.5 hours and a further quantity of 5-[(dimethylamino)methyl]-2-furanmethanol (1.4 g) added. The mixture was heated at 98-100° for 15 min. and the solution neutralised with sodium bicarbonate. Excess of anhydrous sodium carbonate and tetrahydrofuran (100 ml) were added and after 3 hours, the mixture was filtered and the filtrate evaporated in vacuo to give a dark oil. This oil was dissolved in 2-methylpentan-2-one (15 ml), and decolourising charcoal added, before the solution was heated to 98-100° and filtered. The filtrate was evaporated in vacuo and the oily residue was mixed with water (10 ml) at 60°. The mixture was treated with decolourising charcoal and the solution filtered. The filtrate was evaporated to dryness in vacuo to give an oil (0.73 g) consisting of the title compound.

[0014] T.L.C. Silica; methanol:0.88 ammonia (200:1) R_f 0.45 Consistent with a sample prepared according to the method of Example 15 in British Patent Specification No. 1565966.

Claims

1. A process for the preparation of ranitidine of formula (I)

which comprises reacting cystamine of formula (II)

either with a nitroethenamine of formula (III)

where L is alkylthio, or with a compound of formula (IV)

where L is alkylthio, followed by reaction with methylamine, to give a disulphide of formula (V)

which is then reacted with 5-[(dimethylamino)methyl]-2-furanmethanol under acid conditions.

2. A process as claimed in claim 1 wherein the reaction between the disulphide (V) and [(dimethylamino)methyl]-2-furanmethanol is carried out at a temperature of 0 to 100°C.

3. A process as claimed in claim 1 or 2 wherein the reaction between the disulphide (V) and E [(dimethylamino)methyl]-2-furanmethanol is carried out in the presence of hydrochloric acid.

4. A process as claimed in claim 3 wherein the reaction is carried out in the presence of concentrate_l hydrochloric acid at an initial temperature of 0―4.°C, with subsequent heating for a short period 90-100°C.

5. A process as claimed in any of claims 1 to 4 wherein the disulphide (V) is prepared by reaction c cystamine and a nitroethenamine of formula (III) and this reaction is carried out in the presence of a suitabl solvent.

6. A process as claimed in claim 5, wherein the solvent is water.

7. A process as claimed in any of claims 1 to 6 wherein a steady stream of gas is passed through th reaction vessel during preparation of the disulphide.

8. A process as claimed in any of claims 1 to 7 in which the compound of formula (I) is converted into a acid addition salt.

9. A process as claimed in claim 8 in which the acid addition salt is the hydrochloride.

Ansprüche

1. Verfahren zur Herstellung von Rantinidin der Formel (I)

dadurch gekennzeichnet, daß man Cystamin der Formel (11)

entweder mit Nitroethenamin der Formel (111)

worin L Alkylthio ist, oder einer Verbindung der Formel (IV)

worin L Alkylthio ist, umsetzt und anschließend mit Methylamin umsetzt, um ein Disulfid der Formel (V)

welches sodann mit 5-[(Dimethylamino)methyl]-2-furanmethanol unter sauren Bedingungen umgesetzt wird.

2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß die Reaktion zwischen dem Disulfid (V) und dem 5-[(Dimethylamino)methyl]-2-furanmethanol bei einer Temperatur von 0 bis 100°C durchgeführt wird.

3. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß die Reaktion zwischen dem Disulfid (V) und dem 5-[(Dimethylamino)methyl]-2-furanmethanol in Gegenwart von Salzsäure durchgeführt wird.

4. Verfahren nach Anspruch 3, dadurch gekennzeichnet, daß die Reaktion in Gegenwart von konzentrierter Salzsäure bei einer Anfangstemperatur von 0­4°C und unter nachfolgendem Erhitzen über einen kurzen Zeitraum auf 90 bis 100°C durchgeführt wird.

5. Verfahren nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß das Disulfid (V) durch Umsetzung von Cystamin und einem Nitroethenamin der Formel (111) hergestellt wird und daß diese Reaktion in Gegenwart eines geeigneten Lösungsmittels durchgeführt wird.

6. Verfahren nach Anspruch 5, dadurch gekennzeichnet, daß das Lösungsmittel Wasser ist.

7. Verfahren nach einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, daß ein stetiger Strom von Gas durch das Reaktionsgefäß während der Herstellung des Disulfids hindurchgeleitet wird.

8. Verfahren nach einem der Ansprüche 1 bis 7, dadurch gekennzeichnet, daß die Verbindung der Formel (I) in ein Säureadditionssalz umgewandelt wird.

9. Verfahren nach Anspruch 8, dadurch gekennzeichnet, daß das Säureadditionssalz das Hydrochlorid ist.

Revendications

1. Procédé pour la préparation de ranitidine de formule (1)

qui comprend la réaction de la cystamine de formule (II)

soit avec une nitroéthènamine de formule (III)

dans laquelle L est un groupe alkylthio, ou avec un composé de formule (IV)

dans laquelle L est un groupe alkylthio, suivie de la réaction avec la méthylamine, pour donner un bisulfure de formule (V)

que l'on fait ensuite réagir avec le 5-[(diméthylamino)méthyl]-2-furanne-méthanol dans des conditions acides.

2. Procédé selon la revendication 1, dans lequel la réaction entre le bisulfure (V) et le 5-[(diméthylamino)méthyl]-2-furanne-méthanol est réalisée à une température de 0 à 100°C.

3. Procédé selon la revendication 1 ou 2, dans lequel la réaction entre le bisulfure (V) et le 5-[(diméthylamino)méthyl]-2-furanne-méthanol est réalisée en présence d'acide chlorhydrique.

4. Procédé selon la revendication 3, dans lequel la réaction est réalisée en présence d'acide chlorhydrique concentré à une température initiale de 0-4°C, suivie d'un chauffage pendant une courte période à 90―100°C.

5. Procédé selon l'une quelconque des revendications 1 à 4, dans lequel le bisulfure (V) est préparé par réaction d'une cystamine et d'une nitroéthènamine de formule (III) et cette réaction est réalisée en présence d'un solvant convenable.

6. Procédé selon la revendication 5, dans lequel le solvant est l'eau.

7. Procédé selon l'une quelconque des revendications 1 à 6, dans lequel on fait passer un courant régulier de gaz à travers le réacteur pendant la préparation du bisulfure.

8. Procédé selon l'une quelconque des revendications 1 à 7, dans lequel le composé de formule (1) est transformé en sel d'addition avec un acide.

9. Procédé selon la revendication 8, dans lequel le sel d'addition avec un acide est le chlorhydrate.